[RADIOLAB INTRO]

JAD ABUMRAD: Hey, I'm Jad. This is Radiolab. So last week, we heard a story from Molly Webster. It was all about a new, emerging disease. And this week, we're actually gonna go back to Molly.

MOLLY WEBSTER: Well, hello.

JAD: Hey. There you are.

MOLLY: Yay.

JAD: High-five. Yeah.

MOLLY: Hi.

JAD: Because she has some new information about a story that she did a while back about beating back a disease, a disease that's been around for a while.

MOLLY: So...

JAD: We're talking about—well, sorry. You start.

MOLLY: No, we're talking about gamma, which is interesting because gamma was when you were gone.

JAD: Yeah, I remember that.

MOLLY: It was during your sabbatical.

JAD: So here's the deal. It was 2016. I had taken a little break from the show, just a few months. And Molly, along with Robert, decided to do something a little bit different on the show. She actually broke some news. She'd gotten a hot tip about some research that was just out from MIT. And it was about Alzheimer's.

MOLLY: And when I was there, they were in the midst of doing some really exciting follow-up research that they had told me about off the record, but they weren't ready to talk about. But now they are ready...

JAD: Cool.

MOLLY: ...to talk about it.

JAD: Okay, so here's what we're gonna do. We're gonna play the original piece, and then current-day 2020 Molly and Jad will pop in along the way with some updates. But for now, here is 2016 Molly with 2016 Robert.

ROBERT KRULWICH: Hi, I'm Robert Krulwich.

MOLLY: I'm Molly Webster. 

ROBERT: This is Radiolab and today...

MOLLY: We've got breaking news, Robert Krulwich. 

ROBERT: Well, great! This is something we've never done before.

MOLLY: Never done before. 

ROBERT: Well, does anybody know about this yet? 

MOLLY: Well, it is a new bit of research. It's being published today.

ROBERT: Uh-huh.

MOLLY: We've known about it for the last few months, but we haven't been able to talk about it until now.

ROBERT: What's this thing about?

MOLLY: Oh, this is a discovery about Alzheimer's disease.

ROBERT: Uh-huh.

MOLLY: Which I think at this point is something that affects basically every family.

ROBERT: Affected my family, yeah.

MOLLY: Yeah. And this is a discovery that is not a cure, but it's basically about looking at the brain, which is one of the most complicated things in the universe, I think, and poking at it in this super simple way, and getting this bizarre result.

ROBERT: How bizarre?

MOLLY: It's pretty—pretty bizarre.

ROBERT: [laughs]

LI-HUEI TSAI: Hello.

MOLLY: Hello, hello?

LI-HUEI TSAI: Hi, Molly.

MOLLY: Hi.

LI-HUEI TSAI: Hi, how are you?

MOLLY: All right, so last May I was talking to some folks over at the Brain Institute at MIT, and while I was on the phone with them, they started telling me about some research that hadn't been published yet, so it was all very hush hush. It was pretty cool, though. We ended up deciding to sign a non-disclosure agreement, and it was based on the work of this woman Li-Huei Tsai.

LI-HUEI TSAI: Li-Huei Tsai.

MOLLY: Tsai?

LI-HUEI TSAI: Tsai.

MOLLY: Tsai. Okay.

LI-HUEI TSAI: Yeah. I'm a professor and a director of the Picower Institute for Learning and Memory at MIT.

MOLLY: Holy crap. You're the director. How do you have time to do all that? 

LI-HUEI TSAI: I know! That's a good question. [laughs]

MOLLY: She is like a badass, is what she is.

LI-HUEI TSAI: But this is the piece of work I'm very proud of and very excited about.

MOLLY: Okay, cool. So I mean...

LI-HUEI TSAI: So let me—let me begin.

MOLLY: Okay.

LI-HUEI TSAI: So historically, people work on Alzheimer's really focus a lot on...

MOLLY: So I would say generally, when you talk to researchers about Alzheimer's disease, they either focus on...

LI-HUEI TSAI: ...on individual genetic factors,

MOLLY: ...the genetics of the disease, so the genes that predispose you, maybe to Alzheimer's.

LI-HUEI TSAI: Or...

MOLLY: The brain chemistry, and how Alzheimer's affects the chemicals on the brain.

LI-HUEI TSAI: Molecular pathological features.

MOLLY: But in my conversation with Li-Huei, she was talking about something totally different.

LI-HUEI TSAI: We sort of look at it from a different angle.

MOLLY: Her work all centers around something called...

LI-HUEI TSAI: The gamma frequency.

ROBERT: The gamma frequency?

MOLLY: Mm-hmm.

LI-HUEI TSAI: Gamma.

MOLLY: And what is—I'm like, it feels like something from Battlestar Galactica.

LI-HUEI TSAI: [laughs]

MOLLY: So I don't think it's that.

LI-HUEI TSAI: So, this gamma...

MOLLY: You could think of it as a particular beat in your brain.

ROBERT: A beat in the brain.

MOLLY: Yeah.

LI-HUEI TSAI: Yeah.

ROBERT: Which means what, exactly?

MOLLY: Well, just to oversimplify one of the most complicated things in the known universe...

ROBERT: [laughs] Okay, please do.

MOLLY: You've got your brain. It's full of neurons, which are a certain type of brain cell.

LI-HUEI TSAI: We have billions of neurons in the brain.

MOLLY: They have these long tentacles that are reaching out towards other neurons.

LI-HUEI TSAI: And for the brain to function, neurons have to communicate with each other to process information.

MOLLY: And the way they do that is they fire.

LI-HUEI TSAI: Yes.

MOLLY: An electrical signal will go through them and it'll, like, zap another neuron, and it'll turn it on. And then an electrical signal will go through it and it'll zap another neuron, and it'll turn it on. But the cool thing is is that when your brain is doing things like making you move, or write a poem, or think great thoughts, groups of neurons...

LI-HUEI TSAI: Fire in sync.

MOLLY: All together on the same beat. And there's a bunch of different beats that happen in the brain. Some of them are slow, like one beat per second, and that's when you're sleeping. If you're beating around 10 beats per second, like, maybe you're sitting next to a campfire in an Adirondack chair. Or on, like, the totally other end of the spectrum, like, some neurons fire at 600 beats per second.

ROBERT: What are they doing?

MOLLY: That I have no idea.

ROBERT: And all this is going on in your head simultaneously?

MOLLY: Yeah, yeah, yeah. No, that's the cool thing is that when all of these beats in your brain come together, that's when you're able to process the world and understand it as it exists as human beings.

ROBERT: Huh.

MOLLY: But getting back to our story, when your brain is doing something really tricky that requires super focused...

LI-HUEI TSAI: Attention, working memory, and so on.

MOLLY: You're, like, trying to find your way home from the subway station, or if you're in a new city, navigate around it, there's a certain beat that sort of rises above them all, and that is...

LI-HUEI TSAI: The so-called gamma frequency.

MOLLY: This range between 30 beats per second all the way up to 100 beats per second.

LI-HUEI TSAI: And this gamma frequency has been considered to be very important for the higher order cognitive function.

MOLLY: And the interesting thing is that when you look at an Alzheimer's brain, what you see is there's actually less gamma happening, or people say the power of gamma is reduced.

LI-HUEI TSAI: Not all the neurons can be recruited to oscillate at the gamma frequency.

MOLLY: It's still there, it's just quieter.

MOLLY: It's like you turn the volume down.

LI-HUEI TSAI: Right.

ROBERT: All right, so just to briefly sum up here, what we've got is a rhythm, which we call gamma, which is used when we have complicated or higher thoughts in the brain, which when you've got Alzheimer's, kind of gets saggy, or tired. It vanishes.

MOLLY: Yeah. Yeah, totally, and of course, obviously in an Alzheimer's brain, there's a lot going on, and this is just one of the things, right? You've got the plaques that build up around the neurons.

ROBERT: The stuff that gucks up your brain, and makes it hard to think.

MOLLY: Yeah, yeah, yeah. Totally. It's like cobwebs in the brain. And then the connections between neurons gets all muddied, and immune cells get messed up. But Li-Huei Tsai was like, "Forget all that. What would happen if I just bring the gamma back?"

LI-HUEI TSAI: Yeah. We decided to just manipulate gamma oscillations.

ROBERT: And how do you—how do you do that?

MOLLY: Well...

MOLLY: [blows into mic] Hello, hello, hello, hello, hello, hello, hello, hello?

MOLLY: ...technology...

MOLLY: Hi, this is Molly. Hi, hi, hi.

MOLLY: ...technology you can find at the Massachusetts Institute of Technology. And actually I went and took the train up to Boston to MIT not too long ago.

MOLLY: We're walking into the Picower Institute.

MOLLY: It's a...

MOLLY: Wow!

MOLLY: ...big shiny glass building.

LI-HUEI TSAI: Molly, hi! Nice to meet you.

MOLLY: Eventually, Li-Huei Tsai came striding into her office to meet me.

LI-HUEI TSAI: My understanding is that you want to see some of the experimental setup.

MOLLY: And so Li-Huei led me down the hall to this tiny room.

MOLLY: The mice just entered the room!

MOLLY: Brought in these adorable little mice.

MOLLY: Oh, my gosh. They're like little black and soft and furry. Their ears are tagged with a little metal tag on them.

LI-HUEI TSAI: Okay, so...

MOLLY: So here's what they did: they get some mice.

LI-HUEI TSAI: We started off with a mouse model.

MOLLY: Not the mice I actually got all excited over but mice that have an early stage of Alzheimer's disease.

MOLLY: Mice that have an early stage of Alzheimer's disease.

LI-HUEI TSAI: With multiple notable defects.

ROBERT: Do they have the gunky plaque stuff in them yet, or is that later?

MOLLY: No, but they do have...

LI-HUEI TSAI: Elevated levels of beta-amyloid peptides.

MOLLY: Which is this protein that forms the plaques, so it's like basically pre-plaque gunk. But the important thing to Li-Huei Tsai and her team is that they have less gamma going on in their brains. If you remember, the whole plan here is to bring the gamma back.

LI-HUEI TSAI: Yes.

MOLLY: So to do that, they get what might be the world's tiniest drill, and they drill a small hole into the skull of the mouse, and then they take a really thin fiber-optic cable, they slide it through the hole into the brain. And then they get this laser of blue light...

LI-HUEI TSAI: To flicker.

MOLLY: At 40 beats per second.

LI-HUEI TSAI: Gamma frequency.

MOLLY: And they turn that on, and the light travels down the fiber-optic cable, deep down into the brain, to this group of cells that they've modified...

LI-HUEI TSAI: In the hippocampus.

MOLLY: ...to be sensitive to light. So when this pulsing light hit these cells, they actually began to fire at 40 beats per second.

LI-HUEI TSAI: At gamma frequency.

MOLLY: And they would keep these cells firing at gamma...

LI-HUEI TSAI: For one hour.

MOLLY: Firing and firing and firing and firing and firing.

LI-HUEI TSAI: And then after one hour...

MOLLY: They turn off the light, and then eventually they started looking at the brains of these mice, trying to figure out if anything was different after the light flashed. And they see...

LI-HUEI TSAI: To our much surprise...

MOLLY: They were not expecting this at all.

LI-HUEI TSAI: We found...

MOLLY: After they shot this pulsing light into the brain, there was suddenly nearly half as much of that soon-to-be nasty plaque gunk stuff that was filling up their hippocampus.

ROBERT: A half of the...

MOLLY: Yeah.

ROBERT: Half?

MOLLY: Half of the stuff was just swept away.

LI-HUEI TSAI: Yes. 40 to 50 percent reduction of beta amyloid.

MOLLY: That just seems crazy! [laughs]

LI-HUEI TSAI: This is crazy! I mean, we were just so surprised.

ROBERT: Do they know why the flood of light would...

MOLLY: Yeah, yeah. So...

LI-HUEI TSAI: Turn out...

MOLLY: ...the pulsing light somehow triggered the brain's cleanup crew.

LI-HUEI TSAI: Microglia.

MOLLY: These cells in the brain that are called microglia.

LI-HUEI TSAI: You can say they're the janitors of the brain.

MOLLY: And in a normal brain, these janitor cells usually gobble up the gunk.

LI-HUEI TSAI: But in Alzheimer's disease, it's known that microglia, they don't sort of function normally anymore.

MOLLY: It's like these janitors just sort of...

LI-HUEI TSAI: Stop cleaning up.

MOLLY: And go on strike.

ANTHONY MARTORELL: There we go. Okay. Cool.

MOLLY: Okay, so we're looking at a screen that's now flat. It's not...

MOLLY: When I was at MIT, one of Li-Huei's graduate students...

ANTHONY MARTORELL: My name is Anthony Martorell. Second year.

MOLLY: ...was showing me side-by-side comparisons of these mice brains on a screen.

ANTHONY MARTORELL: Can you guess what that is?

MOLLY: Wait, wait. Which part?

ANTHONY MARTORELL: The green thing?

MOLLY: Microglia!

ANTHONY MARTORELL: Microglia, yeah. [laughs]

MOLLY: And you see...

LI-HUEI TSAI: After one hour of gamma...

MOLLY: Wow! So yeah, that part...

LI-HUEI TSAI: ...the microglia, the cell, seems a lot bigger.

MOLLY: Can clearly see these round bodies.

LI-HUEI TSAI: Yeah.

MOLLY: Yep.

LI-HUEI TSAI: Yeah, and also, the belly seems to have more amyloid.

MOLLY: Oh, like they're doing more eating.

LI-HUEI TSAI: Yes, they go back to eat more amyloid again.

MOLLY: It's like somehow making the neurons fire turned on the sanitation system in the brain.

LI-HUEI TSAI: But—but the most wild result...

MOLLY: Wait, there's more wild?

LI-HUEI TSAI: Oh my God! You've gotta hear this.

MOLLY: [laughs] Okay.

LI-HUEI TSAI: Because what I'm about to tell you, you may say, "No, I don't believe it. It's science fiction."

MOLLY: Okay, so one of the things Li-Huei and her team were starting to think was that drilling and fiber-optic cable...

LI-HUEI TSAI: Is very invasive, right?

MOLLY: You'd never be able to do that on a human.

LI-HUEI TSAI: Exactly. So we started to say...

MOLLY: "Well, what if we can get the light into the brain in a different way? Like, maybe we could go through the eyes."

ROBERT: So the hole in your head would be your eyes instead of a hole in your head?

MOLLY: Yeah. Yes.

ROBERT: Hmm.

MOLLY: So Li-Huei and her team created what I like to think of as the flicker room.

MOLLY: Wait, is this the room?

LI-HUEI TSAI: This is the room, and...

MOLLY: Okay.

MOLLY: It turns out, I learned upon my visit, that it is just a storage closet.

MOLLY: You know, you have a—what is this, just a plastic table?

MOLLY: Very DIY.

ANTHONY MARTORELL: Yeah, it's a plastic table you can buy at Target.

MOLLY: There were some plastic shoebox-sized containers lined up on the table for the mice, and then...

LI-HUEI TSAI: You see the strip?

MOLLY: ...around the edge of the table...

LI-HUEI TSAI: Basically, surrounding all the cages.

MOLLY: ...are duct-taped strips of LED lights.

ANTHONY MARTORELL: And the reason why we use LEDs is because a regular light bulb, it can't flash fast enough.

MOLLY: And so the idea is: what if we just put the mice in this room, and just let the light flicker at 40 beats per second?

LI-HUEI TSAI: So you want to show Molly? Like, turn this on?

MOLLY: Yeah!

MOLLY: And so we turn off the overhead light in the room so it's very black, and then...

MOLLY: Oh, wow!

MOLLY: ...the room was now glowing with this white LED light.

ANTHONY MARTORELL: Okay, so the light is turning on and off 40 times a second.

MOLLY: So you don't see anything going, like, on or off. It just looks like something's on, but it kind of feels like my eye is twitching.

LI-HUEI TSAI: Exactly.

MOLLY: And so it's blurring the light a little.

LI-HUEI TSAI: Correct.

MOLLY: Just on the edges, though.

LI-HUEI TSAI: Yeah, just on the edges.

MOLLY: And so they put mice in this room for an hour, and just let them kind of bathe—bathe in this glow.

LI-HUEI TSAI: And guess what?

MOLLY: What?

LI-HUEI TSAI: We look at the amyloid beta levels in the visual cortex, and we found there is a 50 percent reduction.

MOLLY: [gasps] 50 percent?

LI-HUEI TSAI: 50 percent reduction.

MOLLY: Just from shining light in their eyeballs?

LI-HUEI TSAI: Yes!

ROBERT: Wait a second, they didn't do any drilling in their skulls or anything?

MOLLY: No! No, they didn't drill. They didn't tweak the mouses' brain cells to be sensitive to light. This is just...

ROBERT: They just filled the room with occasional LEDs flashing at a particular frequency?

MOLLY: For an hour.

LI-HUEI TSAI: Now do you see? [laughs] Are you going to tell me, "I don't believe it. It's science fiction"?

MOLLY: And they followed this study up with another study which was done in the same way, so the same flicker room, light through the eyeballs. Only this time, they put the mice in there for one hour a day for seven days, and they took mice that had full-blown Alzheimer's. So this is cognitive decline, they're forgetting things, and they've got hardened plaques in their brain. And they see the same thing: nearly half of the stuff was cleared away.

ROBERT: Wow!

MOLLY: Half!

ROBERT: Wow!

LI-HUEI TSAI: It's just flickering light in front of the mice.

MOLLY: I mean, that's the shocking thing. The thing I didn't understand after talking to you about your study was, I was like, "Why hasn't everyone done this before?" Like, why didn't everyone go, "We should just shine light through eyes?"

LI-HUEI TSAI: Well, you know, that's really the most unexpected and exciting aspect of our study, which is something this simple, yet it has never been done before.

MOLLY: One of the things—one of the caveats here is that if you don't do the flicker-light room every 24 hours, the level of gunk in the brain starts going back up again. And so now they're trying to figure out how they can keep those levels down—maybe even for good.

JAD: Okay, current-day Jad here. We'll come back to the original story in a bit and to a big question that all of this work raises. But first, a little update. 2020 Molly recently called Li-Huei Tsai again.

MOLLY: Hello. Hello?

LI-HUEI TSAI: Hello, Molly.

MOLLY: Yay!

JAD: To see what she has been up to since that original research.

MOLLY: How are you?

LI-HUEI TSAI: I'm doing great.

MOLLY: Yeah?

LI-HUEI TSAI: So much new things coming up. And I'm just excited all the time.

MOLLY: [laughs]

MOLLY: And so as I said when I was there in 2016, we had talked a bit off the record. And since then, Li-Huei Tsai has published papers, gone on the record. And what we were talking about is that they were looking to expand their sensory toolkit. So instead of using gamma light, they did...

LI-HUEI TSAI: Gamma sound.

MOLLY: What made you pick sound?

LI-HUEI TSAI: So we know that we can see, we can hear, we can taste, we can smell, we can touch. And among all of this, we figure that sound is relatively straightforward to produce a 40-hertz gamma sound.

JAD: Oh, interesting. So instead of shining a light in the subject's eyes, they would play a tone or something, and it would have the same effect?

MOLLY: Yeah. So they just built a sound that has that same gamma frequency built into it like the lights in the flicker room, and then they play it for the mice.

LI-HUEI TSAI: Yeah.

MOLLY: What is the equivalent of, like, the sound flicker room?

LI-HUEI TSAI: We basically just, you know, add, you know, loudspeakers.

MOLLY: So the sound comes in through the mouse ears.

LI-HUEI TSAI: Right. So there are sensory nerve cells.

MOLLY: Like the waves come in. It gets converted to an electrical signal.

LI-HUEI TSAI: This electrical signal then can be transmitted across the brain circuits.

JAD: So wait, do we know what it sounds like?

MOLLY: I have it here.

JAD: Oh!

MOLLY: So I'm gonna hit play, and then you tell me if you can hear it, 'kay? Oh my God, it's kind of a crazy sound! [laughs] I almost don't want to hit play. Okay. Three, two, one.

[buzzing sound]

JAD: Oh, God!

MOLLY: Yeah.

JAD: Whoa.

MOLLY: Yeah.

JAD: It's like a little insect boring into my brain, and there's like a sub-bass in there that's making my stomach like—ugh!

MOLLY: Right? I—the first time I heard it, I ripped my headphones off my head, and then I—then really converted and found it super soothing.

JAD: I'm not there yet. [laughs]

MOLLY: Okay. I think we should probably also do the caveat of, like, there could be some way in which this comes through your headsets in a weird way. It depends on where the speaker is set. Yada, yada, yada. Where this is not the sound in a way that they are playing.

JAD: Yes, totally. And maybe we'd even want to take it a step further and say, "Do not use this sound." [laughs]

MOLLY: Yes, please do not use this sound at home to self treat. They were playing this for mice. So when they were playing it for mice...

LI-HUEI TSAI: We were able to see very similar effects as those exposed to 40-hertz gamma lights.

MOLLY: They see, like, the—what we talked about in the first episode, which were the microglia, which she calls, like, that the trash picker-uppers of the brain.

LI-HUEI TSAI: They just, you know, completely surround the amyloid plaques.

MOLLY: And so they start eating all that stuff up.

LI-HUEI TSAI: After one to two weeks of exposure, we saw about 30 to 40 percent reduction of the amyloid plaques.

JAD: Wow. So listening to that sound that you just played, just listening to it is a kind of cleansing brain therapy of a kind?

MOLLY: I mean, yes, for mice right now, yes.

JAD: Man!

MOLLY: The interesting thing is is they, as of yet, still have no idea why all this is happening. Why microglia seem to eat more of the trash, they have no idea.

JAD: But they must have some theory, right? Or no?

MOLLY: No.

JAD: No!

MOLLY: And she's done these studies at other rhythms, like...

LI-HUEI TSAI: 41 hertz or 42 hertz or 38 hertz or...

MOLLY: You know, they've tried 80 and they've tried 20. And for some reason, 40 is the sweet spot where you see this activity and you don't see it in other places. But beyond the why—like, why is it 40, or why does gamma do this and nothing else does this, or other things like gamma don't do this—all the new stuff with sound actually leads us to the same question we had in the original episode, the big question which Robert put to me.

ROBERT: If the mouse no longer has quite as much junk in its head, does that mean that it can remember things that had happened to it? It gets mentally more acute?

MOLLY: Yeah. Yeah, that is their big next research. That's what they're...

ROBERT: So they don't know.

MOLLY: They don't know. That's what they're—that is now the next step. But nobody really understands how plaques and the gunk buildup in the brain relates to memory and cognition, and the dogma in the field is that when you have Alzheimer's, you can't form new memories, and once you lose a memory, it's gone for good.

ROBERT: Huh. Okay.

MOLLY: But there is another group at MIT that is actually sort of challenging that assumption that you can never get a memory back.

DHEERAJ ROY: Because the patient could never tell us, we all assumed the information had to be gone.

ROBERT: Oh, really?

MOLLY: Yeah. And we'll get to them. But first we have to go to a break.

JAD: And, of course, we'll be back with more updates right after this.

[LISTENER: Hi, my name is Rachel Mellema, and I'm calling from Alice Springs, Northern Territory, Australia. Radiolab is supported in part by the Alfred P. Sloan Foundation, enhancing public understanding of science and technology in the modern world. More information about Sloan at www.sloan.org.]

[JAD: Science reporting on Radiolab is supported by Science Sandbox, a Simons Foundation initiative dedicated to engaging everyone with the process of science.]

JAD: Hey, Jad here. We are back looking back at Molly Webster's piece from 2016, peppering in some updates as we go. We're gonna keep rolling here with the original for a beat and then we'll get more from current-day 2020 Molly and me in a little bit.

ROBERT: I'm Robert Krulwich.

MOLLY: I'm Molly Webster.

ROBERT: This is Radiolab.

MOLLY: And we're back.

ROBERT: And just before the break, you said that there may be a way to bring a memory back from Alzheimer's disease.

MOLLY: Mm-hmm.

ROBERT: To pull the memory back into place.

MOLLY: Yeah.

DHEERAJ ROY: Why are we so quick to jump to the conclusion that the information was somehow completely gone?

MOLLY: And the person who said that to me is this guy.

DHEERAJ ROY: I'm Dheeraj Roy. I'm a fourth-year graduate student in the Susumu Tonegawa Lab.

MOLLY: Over at the Tonegawa Lab, they were thinking, "What if we could figure out exactly where the memory should be in the brain, and just give that spot a little bit of juice?"

DHEERAJ ROY: Right.

MOLLY: So they took some mice that were just starting to lose their ability to remember things, and they thought, "Okay, let's try to give them a memory."

DHEERAJ ROY: We put them in a box that has a particular smell, some sort of lighting, and some texture on their feet.

MOLLY: A little mouse carpet, or...[laughs]

DHEERAJ ROY: That's exactly what it is.

MOLLY: Wait, really?

DHEERAJ ROY: Yeah. [laughs]

MOLLY: Okay, mice on carpets. Got it.

MOLLY: The point is the box looks and feels and smells different than any other box they would hang out in.

DHEERAJ ROY: And then we give them a light electrical shock.

MOLLY: And the mice, they just freeze.

DHEERAJ ROY: They don't move at all.

MOLLY: Which is a sign that they're afraid.

DHEERAJ ROY: They hate the box.

MOLLY: And for the rest of the afternoon—which is a very long time in mouse time—they go on hating the box, which means with the carpet and the light and the smell, if you put it back in there, it'll freeze because it remembers the shock.

DHEERAJ ROY: Yes.

MOLLY: But...

DHEERAJ ROY: A day or a week later...

MOLLY: When these same mice were put back into the same box...

DHEERAJ ROY: Instead of being scared of the box, they would just continue investigating as if nothing happened. They could not remember.

MOLLY: So Dheeraj and his team did what Li-Huei did: they got some modified mice, and then they put a little hole in their head. They slid in a fiber-optic cable. They shined some light to trigger the neurons that they think hold this memory. And they were...

ROBERT: In the fear section.

MOLLY: Near the fear section. So leading on the path to the fear section.

DHEERAJ ROY: So we do this...

MOLLY: And then...

DHEERAJ ROY: Put them back into the box.

MOLLY: The box with the particular lighting and smell and carpet.

DHEERAJ ROY: And ask is there any change in their behavior?

MOLLY: Will they act afraid again?

DHEERAJ ROY: Do they show any more memory? And they did.

MOLLY WEBSTER: Wait. Shut up. They actually were scared of the box again?

DHEERAJ ROY: Exactly. They showed recovered memory.

MOLLY: Wow!

ROBERT: Whoa.

MOLLY: So that's like—bam, that memory's in there.

DHEERAJ ROY: Exactly. Voila, the behavior was back.

ROBERT: You can dig up the memory by shining light in the right place?

MOLLY: Yeah.

DHEERAJ ROY: Mm-hmm.

MOLLY: I was always under the impression that the memories were totally lost.

DHEERAJ ROY: Right. So I think that's not just you. I think that's essentially the entire field, what you described.

MOLLY: Oh, okay. Well, that's good.

DHEERAJ ROY: Just because the patient could never tell us, we all assumed the information had to be gone.

ROBERT: Huh.

MOLLY: So one of the things to say is that Dheraj did tell me that, you know, all the experiments they did are in mice that have early Alzheimer's. The thought is, though, is that once you get to the late stage of the disease, there's enough damage in the brain that you really wouldn't be able to get those memories back.

ROBERT: That might be right, that a memory loss is just lost. But when you have someone in your house and you live with this disease day in and day out, the disease just goes its own way.

MOLLY: Mm-hmm.

ROBERT: And it can puzzle you or frighten you or suddenly declare something new that you didn't expect. So for example, my dad had it for about nine, ten years. It was a slow act of disappearing that he did. I mean, the last time my father came to was so far into the disease, he hadn't spoken for a year and a half. He was sitting at the table for the Passover Seder, and there's a song that you sing, and it goes [singing]. So it's just a chorus, and from out of nowhere, this being at the end of the table who I knew was my father, who hadn't spoken in a year and a half or two, and had not spoken coherently for three, suddenly flew into the song, and sang the song full-throatedly at the table, like the reappearance of some last figment of himself. And it was—it was both horrifying and extraordinary. Both.

DHEERAJ ROY: I mean, I think that's—the fact that maybe some information still persists, hopefully someday we could kind of—maybe there's something we could do. But yeah, this is all in my mind at the moment.

LI-HUEI TSAI: As long as we can figure out how to rebuild the pathway to retrieve the memory, then I think there is hope.

MOLLY: And then I want to jump in here with one more part of the sound update, which is that Li-Huei and her team in particular are thinking about it in regard to capturing memories. Because where this research probably gets even, like, more interesting is when you do the light flashing and that sound at the same time.

LI-HUEI TSAI: We eventually just decided why don't we, you know, put the two together and see how the animals respond?

MOLLY: This is becoming like a mice spa.

LI-HUEY TSAI: [laughs]

MOLLY: And when they did that, they saw this gamma beat in the brain, but not just in the auditory cortex or the visual cortex.

LI-HUEY TSAI: Not just in one particular brain region, now we are seeing across different brain regions.

MOLLY: So the hippocampus got involved and the prefrontal cortex got involved. And then there was the neocortex and maybe even the parietal lobes. So there was, like, activity, like, all across the brain.

JAD: Is it a little bit like a whole bunch of clocks coming into sync?

MOLLY: Yeah. Yeah. And imagine thinking it's only gonna affect one clock, but it actually somehow pulls them all into synchrony. Again, they saw the microglia doing their cleanup thing all across the brain, but they also saw almost like a rebuilding of neuronal circuitry. So, like, the synapses between neurons seemed to improve.

LI-HUEI TSAI: Then basically, this repaired the disrupted neurocircuitry, and I think this in turn, can lead to recovery of learning a memory.

MOLLY: And what she's been finding with mice is that it seems to. Basically, in a way, she's done something very similar to what Dheeraj has done, but with her own light and sound technique, and the memories came back.

JAD: That's so interesting!

LI-HUEI TSAI: And the mice show very impressive improvement to their cognitive ability.

MOLLY: So it's almost like two things happening, which is you're seeing physiological effects in the brain, and then you're seeing the layer on top of that, which is then the memories that live in the physiology are also having some impact.

LI-HUEY TSAI: Yes.

MOLLY: So with all this stuff—super new, so I feel like it's caveat time. And for the caveat, I am gonna throw back to the caveat we had in the original piece.

LI-HUEI TSAI: You know, I personally think the most important question is whether humans respond similarly.

MOLLY: I mean, keep in mind that both Dheeraj's study and Li-Huei Tsai's are in mice, not humans.

LI-HUEI TSAI: Right, so I...

MOLLY: And do you have a thought that why—like, is there a reason that a human neuron might react differently than a mouse?

LI-HUEI TSAI: The thing is, I think especially, you know, in Alzheimer's field, I mean, people got burned a lot.

MOLLY: You know, there's like a 99.6 percent failure rate in moving something that seemed to work in mice to humans in Alzheimer's.

ROBERT: 99.6?

MOLLY: Yeah. Yeah, that was a study that came out in 2012.

ROBERT: That's a horrible number.

LI-HUEI TSAI: So I just gotta be really conservative.

MOLLY: I'll dial it back. I'll dial it back.

LI-HUEI TSAI: You know, what we have in mice, it's just so exciting and so unexpected, so much fun but, you know, I'm gonna keep my mind open when it comes to humans.

MOLLY: The plan is that we're gonna find out because they're going straight to humans.

ROBERT: Oh, so they're gonna do human trials.

MOLLY: Well, they want to. So yeah, I guess we'll see. And so we have my final final update, which is that Li-Huei Tsai and her crew have indeed started human trials.

LI-HUEI TSAI: So we indeed managed to get an RB approved for our first very small scale study in early stage Alzheimer's disease subjects.

MOLLY: They're doing a clinical trial with 15 Alzheimer's patients.

JAD: How far into the study are they?

MOLLY: I talked to Li-Huai in January, and they had some people enrolled.

LI-HUEI TSAI: So we have recruited 15 individual people. We basically installed our light and sound device in their home.

MOLLY: Really?

LI-HUEI TSAI: Yeah. So they themselves or their caregiver can turn on the device.

MOLLY: And then they sit there and they get the light flashed in their eyes, and they get the sound flashed at their ears. And they're doing it an hour a day for six to eight months, maybe six to nine months, and they're just collecting data and I guess we're gonna see.

LI-HUEI TSAI: You know, we are talking about living human beings. It's not that we can just take out their brain and see their microglia or all this, but we are evaluating all of the subjects in terms of their cognitive ability, and we also do MRI scan to look at how active their brain activity is.

JAD: And do you have any intel on what they're seeing so far?

MOLLY: Nada. I wish.

LI-HUEI TSAI: I mean, every step of the way, to be quite honest, it's always a surprise. It's like, oh, gamma can do this and gamma can do that. You know, I think that the journey is like a magic carpet ride.

ROBERT: This is the glorious part of all this, this organ of ours, the brain, is so crazily complicated with, like, whatever, 100-trillion connections or whatever it is. There's so much chance there's gonna be a lot of surprise!

MOLLY: Yeah. It's like almost even if it doesn't lead to any treatment in humans or something super concrete, it's like we know this little secret about the brain now, and there's something that feels beautiful in that.

LI-HUEI TSAI: Yeah, I'm actually setting this up for my Christmas tree.

MOLLY: Are you really?

LI-HUEI TSAI: Yes. Yeah, we—I just bought the new LED lights, and they can flicker a different color, with different colors.

MOLLY: Oh, so each individual bulb can travel through colors, but while they're doing that, they're gonna be flickering at 40.

LI-HUEI TSAI: We're gonna have a very therapeutic Christmas. [laughs]

MOLLY: In the Li-Huei Tsai household? This is the tree in your home?

LI-HUEI TSAI: Yes. Yes.

MOLLY: I want to have an eggnog next to that tree.

ROBERT: Yeah.

JAD: Hey. I'm Jad Abumrad.

ROBERT: I'm Robert Krulwich.

MOLLY: And this year, they might even add some 40-gamma jingle bells. Who knows?

JAD: Wow. So cool.

MOLLY: And that's the update.

JAD: Yeah. Thank you. Thank you, Molly. Obviously, this update was reported by Molly Webster, and it was produced by Rachael Cusick. And of course, don't say this enough, big props to Soren Wheeler. Special thanks to Dheeraj Roy. I am Jad Abumrad, just a man who longs for the 40-kilohertz calming hum of the gamma. I shall go and listen to that sound now. In the meantime, thank you for listening. See you next week.

[LISTENER: Hi. This is Verity, calling from Bristol in the UK. Radiolab is created by Jad Abumrad with Robert Krulwich and produced by Soren Wheeler. Dylan Keefe is our director of sound design. Suzie Lechtenberg is our executive producer. Our staff includes: Simon Adler, Jeremy Bloom, Becca Bressler, Rachael Cusick, David Gebel, Bethel Habte, Tracie Hunte, Matt Kielty, Tobin Low, Annie McEwen, Latif Nasser, Sarah Qari, Arianne Wack, Pat Walters and Molly Webster, with help from Shima Oliaee, Sarah Sandbach and Russell Gragg. Our fact-checker is Michelle Harris.]

 

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